The major hypothesis of this study is that a constellation of individually sub-pathological cardiovascular alterations acts in concert to initiate and sustain the elevated blood pressure seen in hypertension. Specifically, we proposed that different systemic and microvascular reactivities lead to distinctive hemodynamic responses to environmental stressors and stimuli. The pattern of individual hemodynamic responses then determines the more long-term vascular structural alterations which provide the basis for chronic elevation in total peripheral resistance. During previous years, we have identified vascular defects in the spontaneously hypertensive rat (SHR) and untreated human essential hypertensives. The most significant defects are a reduced arteriolar growth and an increase in cardiac index during the developmental phase of hypertension. Our long-term goal is to explore the possibility that the control of vessel growth and the factors causing the increased cardiac index are involved in the hypertension initiation and maintenance processes, and to investigate the mechanisms whereby this occurs. We propose to test the above-stated hypotheses by performing four sets of investigations: 1) A study of the systemic and microvascular reactivity to volume, sound and restraint stressors and endogenous neuroendocrine stimuli. The experiments will be carried out in chronically instrumented, unanesthetized animals. 2) Investigations of vasoactive agent interactions will be carried out on arterioles and venules by utilizing a novel technique for the application of one agent to the tissue side and another agent to the intravascular side of the cremaster muscle. 3) Experiments will be conducted to determine the mechanism(s) regulating tissue vascularity by chronic application or removal of agents and stimuli suspected in local control of blood flow and/or vessel growth. And, 4) A correlaction between the results of our animal studies with human hemodynamic and microvascular alterations will be performed in a control and drug treatment group of patients in our Hypertension Outpatient Clinic. These studies offer the potential for a better understanding of some of the basic mechanisms involved in the hypertensive process and mechanism(s) regulating vascularization.